NO156201B - A STREPTOMYCES METABOLITE M139603 WHICH, BY ADDING TO LINES, IMPROVES THE GROWTH SPEED OF DRUGS. - Google Patents
A STREPTOMYCES METABOLITE M139603 WHICH, BY ADDING TO LINES, IMPROVES THE GROWTH SPEED OF DRUGS. Download PDFInfo
- Publication number
- NO156201B NO156201B NO792537A NO792537A NO156201B NO 156201 B NO156201 B NO 156201B NO 792537 A NO792537 A NO 792537A NO 792537 A NO792537 A NO 792537A NO 156201 B NO156201 B NO 156201B
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- Norway
- Prior art keywords
- compound
- mixture
- days
- ethyl acetate
- drugs
- Prior art date
Links
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
- C12P1/06—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using actinomycetales
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/195—Antibiotics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/465—Streptomyces
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P60/00—Technologies relating to agriculture, livestock or agroalimentary industries
- Y02P60/20—Reduction of greenhouse gas [GHG] emissions in agriculture, e.g. CO2
- Y02P60/22—Methane [CH4], e.g. from rice paddies
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Animal Husbandry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Fodder In General (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Feed For Specific Animals (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Compounds Of Unknown Constitution (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
Description
Foreliggende oppfinnelse gjelder en metabolitt, M139603, The present invention relates to a metabolite, M139603,
som oppnås fra den aerobe kultur av Streptomyces longisporoflavus og som er en ny forbindelse med formelen C^H^OgNa. M139603 er et natriumsalt, og oppfinnelsen gjelder også den tilsvarende "frie syre" og andre alkalimetallsalter som kan oppnås derfra. Forbind- which is obtained from the aerobic culture of Streptomyces longisporoflavus and which is a new compound with the formula C^H^OgNa. M139603 is a sodium salt, and the invention also applies to the corresponding "free acid" and other alkali metal salts that can be obtained therefrom. Connect-
elsene er effektive for å redusere mengden metan som frembringes ved fermentering i rumen, og øke mengden propionsyre i rumenvæsken hos kveg, og antas derfor å ha vekstfremmende egenskaper hos drøv- the alders are effective in reducing the amount of methane produced by fermentation in the rumen, and increasing the amount of propionic acid in the rumen fluid in cattle, and are therefore believed to have growth-promoting properties in ruminants
tyggere, idet det er vel kjent at andre kjemiske forbindelser som øker propionsyrenivået i rumenvæsken resulterer i økede vekstrater når det gis i foret til kveg eller sauer. Forbindelsen M139603 ruminants, as it is well known that other chemical compounds that increase propionic acid levels in the rumen fluid result in increased growth rates when fed to cattle or sheep. The compound M139603
har strukturformelen has the structural formula
hvor where
A er hydrogen eller et alkalimetall. A is hydrogen or an alkali metal.
Forbindelsen ifølge oppfinnelsen har følgende egenskaper: The compound according to the invention has the following properties:
(a) molekylf orme 1 C^H^OgNa som indikert ved massespektrometri , (a) molecular form 1 C^H^OgNa as indicated by mass spectrometry,
som viser et molekylært ion, M<+>, med masse 624 , 361 (beregnet for <C>^Hj-^<OgN>a = 624,364), og ved elementæranalyse: which shows a molecular ion, M<+>, with mass 624 , 361 (calculated for <C>^Hj-^<OgN>a = 624,364), and by elemental analysis:
C = 67,5, H = 8,8% (beregnet for C^<H>^OgNa: C = 67,3, C = 67.5, H = 8.8% (calculated for C^<H>^OgNa: C = 67.3,
H = 8,5%) ; H = 8.5%) ;
(b) infrarødt spektrum i nujol "mull", som vist i figur 1, med karakteristiske absorpsjoner ved 3300, 1725, 1645, 1565 og (b) infrared spectrum in nujol "mull", as shown in Figure 1, with characteristic absorptions at 3300, 1725, 1645, 1565 and
915 cm<-1>; 915 cm<-1>;
(c) proton-magnetisk resonans-spektrum i deuteriokloroform som vist i figur 2; (d) ultrafiolett-spektrum i etanol-løsning viser karakteristiske absorpsjoner ved 234 nm (e = 12900) og 272 nm (r. = 10800) ; (e) smeltepunkt 176-8°C; (f) fa]p<3> = -82° (c = 0,2 i metanol); (c) proton magnetic resonance spectrum in deuteriochloroform as shown in Figure 2; (d) ultraviolet spectrum in ethanol solution shows characteristic absorptions at 234 nm (e = 12900) and 272 nm (r. = 10800); (e) melting point 176-8°C; (f) fa]p<3> = -82° (c = 0.2 in methanol);
og den tilsvarende "frie syre"-formen derav med molekylformelen <C>35H54°8' karakter:i-sert ved Rp 0,55 (omtrentlig) ved tynnskiktkromatografi på silikagel (Merck's "kiselgel 60F-254") med 0,25 mm tykkelse og utviklet med en blanding av dietyleter, metanol og maursyre i forholdet 95:4:1 volumdeler; UV i etanol 274 nm and the corresponding "free acid" form thereof with the molecular formula <C>35H54°8' characterized at Rp 0.55 (approximately) by thin layer chromatography on silica gel (Merck's "silica gel 60F-254") with 0.25 mm thickness and developed with a mixture of diethyl ether, methanol and formic acid in the ratio 95:4:1 parts by volume; UV in ethanol 274 nm
(e = 13900), bredt; og andre alkalimetallsalter som kan oppnås derfra. (e = 13900), wide; and other alkali metal salts obtainable therefrom.
Ovennevnte forbindelse kan fremstilles ved å The above compound can be prepared by
dyrke en M139603-produserende stamme av Streptomyces longisporoflavus, eller en Ml39603-produserende variant eller mutant derav, i et vandig næringsmedium inneholdende en kilde for assimilerbart karbon, under rystede, aerobe betingelser ved en temperatur på grow an M139603-producing strain of Streptomyces longisporoflavus, or an Ml39603-producing variant or mutant thereof, in an aqueous nutrient medium containing a source of assimilable carbon, under shaken, aerobic conditions at a temperature of
mellom 22 og 32°C, ekstrahere fermenteringsblandingen oppnådd på denne måten med et vannblandbart, organisk løsningsmiddel ved konvensjonelle metoder, og fordampe løsningsmidlet, hvorefter natriumsaltet av M138603 om ønsket kan omdannes til den "frie syren", og den "frie syren" kan omdannes til andre alkalimetallsalter ved konvensjonelle metoder. between 22 and 32°C, extract the fermentation mixture thus obtained with a water-miscible organic solvent by conventional methods, and evaporate the solvent, after which the sodium salt of M138603 can be converted into the "free acid" if desired, and the "free acid" can be converted to other alkali metal salts by conventional methods.
En egnet M139603-produserende stamme av S. longisporoflavus er den som identifiseres som NCIB 11426, som er tilgjengelig uten innskrenkninger fra National Collection of Industrial Bacteria, Ministry of Agriculture, Fisheries and Food, Torry Research A suitable M139603-producing strain of S. longisporoflavus is that identified as NCIB 11426, which is available without restriction from the National Collection of Industrial Bacteria, Ministry of Agriculture, Fisheries and Food, Torry Research
Station, 135 Abbey Road, Aberdeen AB9 8DG, Skottland, og som Station, 135 Abbey Road, Aberdeen AB9 8DG, Scotland, and which
har følgende beskrivelse: has the following description:
[De media som brukes er sammensatt overensstemmende med oppskriftene for "International Streptomyces Project" (ISP) og er som beskrevet av Shirling, E.G. & Gottlieb, D (International Journal of Systematic Bacteriology, 16 (3), 313-340, 1966)]. Betingelser ved inkuberingen: ca. 25°C [The media used are composed in accordance with the recipes of the "International Streptomyces Project" (ISP) and are as described by Shirling, E.G. & Gottlieb, D (International Journal of Systematic Bacteriology, 16 (3), 313-340, 1966)]. Incubation conditions: approx. 25°C
dagslys. daylight.
I SPl Trypton-gjær (men med tilsatt agar) I SPl Tryptone yeast (but with added agar)
5 dager - Tynn, litt fuktig, fløyelsaktig, lys brun. 5 days - Thin, slightly moist, velvety, light brown.
- Motsatt side uf?rvet. - Opposite side undyed.
13 dager - Tynn fløyelsaktig - svakt granulær, lys brun. 13 days - Thin velvety - slightly granular, light brown.
- Motsatt side ufarvet. - Opposite side uncoloured.
ISP2 Gjærekstrakt/maltekstrakt-agar ISP2 Yeast extract/malt extract agar
5 dager - Tynn, fløyelsaktig, lysegrå 5 days - Thin, velvety, light gray
- Motsatt side, meget blek, gul, lysbrun. - Opposite side, very pale, yellow, light brown.
13 dager - Antagelig, hevet og rynket, fløyelsaktig, lysegul/brun/ grå 13 days - Presumably, raised and wrinkled, velvety, pale yellow/brown/grey
- Motsatt side - lysebrun - Opposite side - light brown
ISP3 Havremel-agar ISP3 Oatmeal agar
5 dager - Sparsom til tynn, fløyelsaktig, lysegul/grå 5 days - Sparing to thin, velvety, pale yellow/grey
- Motsatt side ikke synlig - Opposite side not visible
13 dager - Tynn, svakt hevet, fløyelsaktig, lysegrå 13 days - Thin, slightly raised, velvety, light gray
- Bakside ikke synlig - Back side not visible
ISP4 Uorganiske salter - start-agar ISP4 Inorganic salts - starter agar
5 dager - Tynn, lysebrun, svakt granulær - Bakside ufarvet 5 days - Thin, light brown, slightly granular - Back uncoloured
13 dager - Tynn, litt fuktig, lysebrun 13 days - Thin, slightly moist, light brown
- Bakside mer eller mindre ufarvet. - Back side more or less uncoloured.
ISP5 Glycerol-asparagin-agar ISP5 Glycerol-asparagine agar
5 dager - Tynn, svakt granulær, lysebrun - Bakside ufarvet 5 days - Thin, slightly granular, light brown - Back uncoloured
13 dager - Tynn, fløyelsaktig, lysegrå 13 days - Thin, velvety, light gray
- Bakside - ufarvet - Back - uncoloured
I SP7 Tyrosin-agar In SP7 Tyrosine Agar
5 dager - Tynn til sparsom, svakt granulær, fløyelsaktig, lysebrun/grå 5 days - Thin to sparse, slightly granular, velvety, light brown/grey
- Bakside ufarvet - Back uncoloured
13 dager - Tynn, fløyelsaktig, svakt hevet, lysebrun 13 days - Thin, velvety, slightly raised, light brown
- Bakside - lysebrun/grå - Back - light brown/grey
Med ISP7 blir kulturen med tiden generelt mer rosa-lysebrun, men viser noen områder med mørkere farve, forbundet med kraftigere sporedannelse. With ISP7, the culture generally becomes more pinkish-light brown with time, but shows some areas of darker color associated with stronger sporulation.
ISP9 - Karbonutnyttende agar ISP9 - Carbon utilizing agar
Generelt Generally
Ingen melaniner fremstilles No melanins are produced
Ingen motsatte pigmenter fremstilles. No opposing pigments are produced.
Ingen løselige pigmenter fremstilles. No soluble pigments are produced.
Sporer bæres i åpne og tette spiraler, ofte separert fra hoved-aksen ved en rettholder som bærer "hypha" eller kanskje en sporekjede. Sporene er selv ganske vanskelige å se med normal mikroskopi idet de er meget tett forent med hverandre. Spore-veggene (E. M. på 4% uranylacetat-preparat) er glatte. Spores are borne in open and close whorls, often separated from the main axis by a recumbent bearing "hypha" or perhaps a spore chain. The spores themselves are quite difficult to see with normal microscopy as they are very closely united with each other. The spore walls (E.M. on 4% uranyl acetate preparation) are smooth.
Denne stamme av S. longisporoflavus er også tilgjengelig uten innskrenkning fra Centraalbureau voor Schimmelcultures, PO Box 273, Oosterstraat 1, 3740 AG Baarn, Nederland, under referanse CBS 312.79. This strain of S. longisporoflavus is also available without restriction from Centraalbureau voor Schimmelcultures, PO Box 273, Oosterstraat 1, 3740 AG Baarn, The Netherlands, under reference CBS 312.79.
Foruten Streptomyces longisporoflavus NCIB 11426, kan man også anvende andre M139603-frembringende varianter og mutanter derav. Besides Streptomyces longisporoflavus NCIB 11426, other M139603-producing variants and mutants thereof can also be used.
Forbindelsen kan anvedes i form av den fermenteringsblanding som oppnås ved å dyrke en Ml39603-produserende stamme av Streptomyces longisporoflavus NCIB 11426, eller en M139603-produserende variant eller mutant derav. The compound can be used in the form of the fermentation mixture obtained by growing an M139603-producing strain of Streptomyces longisporoflavus NCIB 11426, or an M139603-producing variant or mutant thereof.
Forbindelsen kan også anvendes i form av en ekstrakt som oppnås ved å dyrke en Ml3960 3-produserende stamme av Streptomyces longisporoflavus NCIB 11426, eller en M139603-produserende variant eller mutant derav, som beskrevet ovenfor, og ekstrahere fermenteringsblandingen med et vannblandbart, organisk løsningsmiddel, som f.eks. etylacetat. The compound can also be used in the form of an extract obtained by growing an Ml3960 3-producing strain of Streptomyces longisporoflavus NCIB 11426, or an M139603-producing variant or mutant thereof, as described above, and extracting the fermentation mixture with a water-miscible organic solvent, like for example. ethyl acetate.
Den "frie syre" som tilsvarer natriumsaltet, M139603, The "free acid" corresponding to the sodium salt, M139603,
kan oppnås ved surgjørinq av en løsning av M139603 og ckstrahering av den sure løsningen med et vannblandbart, organisk løsningsmiddel; og andre alkalimetallsalter kan oppnås ved behandling av en løsning av den "frie syren" med et egnet alkalimetallhydroksyd, f.eks. litiumhydroksyd, kaliumhydroksyd, cesiumhydroksyd eller rubidiumhydroksyd. Dersom det anvendes natriumhydroksyd, regenereres M139603, hvilket viser at det ikke foregår noen strukturell forandring i disse reaksjoner. can be achieved by acidifying a solution of M139603 and extracting the acidic solution with a water-miscible organic solvent; and other alkali metal salts can be obtained by treating a solution of the "free acid" with a suitable alkali metal hydroxide, e.g. lithium hydroxide, potassium hydroxide, cesium hydroxide or rubidium hydroxide. If sodium hydroxide is used, M139603 is regenerated, which shows that no structural change takes place in these reactions.
Som konstatert ovenfor har forbindelsene den virkning As noted above, the compounds have that effect
at dé øker mengden propionsyre i rumenvæsken,. og øker spesielt mengden propionsyre på bekostning av metan og/eller eddiksyre. Dette er kjent for å være en ønskelig virkning i drøvtygger-ernæring, fordi propionsyre er en meget mer effektiv forløper for glukose, fra hvilken dyrene oppnår sin energi og vekst, enn eddiksyre; mens den del av dyrets forinntak som omdannes til metan, ganske enkelt går tapt for dyret, idet metanet utskilles ved raping. Modifisering av rumen-metabolismen som forårsakes av forbindelsene fremstilt ifølge oppfinnelsen er således en meget nyttig virkning, og antas å øke veksthastigheten og for-omdannelseseffektiviteten hos drøvtyggende dyr. that it increases the amount of propionic acid in the rumen fluid. and especially increases the amount of propionic acid at the expense of methane and/or acetic acid. This is known to be a desirable effect in ruminant nutrition, because propionic acid is a much more efficient precursor of glucose, from which animals derive their energy and growth, than acetic acid; while the part of the animal's intake that is converted into methane is simply lost to the animal, as the methane is excreted by belching. Modification of the rumen metabolism caused by the compounds produced according to the invention is thus a very beneficial effect, and is believed to increase the growth rate and fore-conversion efficiency in ruminants.
Forbindelsen eller en komposisjon inneholdende denne The compound or a composition containing it
kan således anvendes ved nold av drøvtyggere for å øke deres veksthastighet og/eller øke effektiviteten ved deres forom-dannelse, hvilken omfatter oral administrering av en forbindelse, formenteringsprodukt eller -ekstrakt ifølge oppfinnelsen som beskrevet ovenfor, til dyrene. can thus be used in the breeding of ruminants to increase their growth rate and/or increase the efficiency of their foraming, which comprises oral administration of a compound, fermentation product or extract according to the invention as described above to the animals.
Forbindelsene administreres fortrinnsvis oralt til The compounds are preferably administered orally to
dyrene som et tillegg til deres normale diett, dvs. sammenblandet med et vanlig, fast for, i forblokker eller saltslikkestener oppløst i drikkevannet eller, for unge dyr som f.eks. lam eller kalver, oppløst i helmelk eller skummet melk. Forbindelsene innblandes i for, forblokker, saltslikkestener, drikkevann, helmelk eller skummet melk i en slik mengde at hvert behandlet dyr vil fortære fra 0,01 til 30 mg/kg kroppsvekt pr. the animals as an addition to their normal diet, i.e. mixed with a regular, solid feed, in pre-blocks or salt lick stones dissolved in the drinking water or, for young animals such as e.g. lamb or calves, dissolved in whole milk or skimmed milk. The compounds are mixed into feed, feed blocks, salt licks, drinking water, whole milk or skimmed milk in such a quantity that each treated animal will consume from 0.01 to 30 mg/kg body weight per
dag, fortrinnsvis fra 0,01 til 10 mg/kg pr. dag, av en forbindelse fremstilt ifølge oppfinnelsen. day, preferably from 0.01 to 10 mg/kg per day, of a compound produced according to the invention.
Dyrene kan motta forbindelsene ifølge oppfinnelsen The animals can receive the compounds according to the invention
i hovedsak i hele sin vekstperiode, eller i bare en del av denne periode, f.eks. den første del og/eller den periode som fører mainly during its entire growth period, or during only part of this period, e.g. the first part and/or the period leading up to it
frem til slakt. Økningen i veksthastighet, oppnådd ved å bruke metoden ifølge oppfinnelsen, muliggjør at dyr som oppfores for kjøttproduksjon, kan bringes til slakte- eller markedsvekt i løpet av en kortere vekstperiode enn normalt eller det produ-seres tyngre dyr ved slutten av en normal vekstperiode. Den for-bedrede effektivitet ved f5romdannelsen som oppnås ved å anvende metoden ifølge oppfinnelsen, gjør det mulig for behandlede dyr å oppnå en ønsket vekt ved konsum av mindre for enn ubehandlede dyr som vokser til samme vekt. Ved optimale vekstfremmende nivåer observeres det ingen toksisk effekt på grunn av forbindelsene fremstilt ifølge oppfinnelsen. until slaughter. The increase in growth rate, achieved by using the method according to the invention, enables animals raised for meat production to be brought to slaughter or market weight during a shorter than normal growth period or heavier animals are produced at the end of a normal growth period. The improved efficiency of the foam formation which is achieved by using the method according to the invention makes it possible for treated animals to achieve a desired weight by consuming less fat than untreated animals that grow to the same weight. At optimal growth-promoting levels, no toxic effect is observed due to the compounds produced according to the invention.
Ifølge et ytterligere trekk ved oppfinnelsen tilveie-bringes et preparat som omfatter den nye forbindelse eller et fermenteringsprodukt eller en fermenteringsekstrakt inneholdende denne, sammen med et fast eller flytende, spiselig, ikke- According to a further feature of the invention, a preparation comprising the new compound or a fermentation product or a fermentation extract containing this is provided, together with a solid or liquid, edible, non-
toksisk fortynningsmiddel eller bærer. toxic diluent or carrier.
En egnet, flytende fortynner eller bærer er eksempelvis drikkevann, helmelk eller skummet melk. A suitable liquid diluent or carrier is, for example, drinking water, whole milk or skimmed milk.
En egnet, fast, spiselig, ikke-toksisk fortynner eller bærer kan eksempelvis være et konvensjonelt, ernæringsmessig avveiet forstoff for drøvtyggere, f.eks. en typisk kveg- eller saue-diett bestående av kornprodukter, som f.eks. byggmcl, maismel eller hvetefor, nøtte- og frø-produkter, som f.eks. avskallet jordnøttkake eller bomullsfrøkake, eller ekstrahert bomullsfrøkake, sammen med mindre mengder av eksempelvis fjærmel, tangmel, benmel, kritt, salt, urinstoff, melasse, vitaminer og spormineraler; eller den kan være en inert, fast fortynner eller bærer uten energiverdi, f.eks. kaolin, talk, kalsiumkarbonat, valkejord, attapulgitt-leire, malte østersskjell eller malt kalksten; eller den kan være stivelse eller laktose. A suitable, solid, edible, non-toxic diluent or carrier can, for example, be a conventional, nutritionally balanced precursor for ruminants, e.g. a typical cattle or sheep diet consisting of cereal products, such as barley flour, maize flour or wheat feed, nut and seed products, such as e.g. shelled peanut cake or cottonseed cake, or extracted cottonseed cake, together with smaller amounts of, for example, feather meal, seaweed meal, bone meal, chalk, salt, urea, molasses, vitamins and trace minerals; or it may be an inert, solid diluent or carrier of no energy value, e.g. kaolin, talc, calcium carbonate, loam, attapulgite clay, ground oyster shells or ground limestone; or it may be starch or lactose.
Preparatet ifølge oppfinnelsen kan ha form av et for med tilsetninger for direkte foring til dyr, i hvilket tilfelle det vil inneholde fra 5 til 3000 ppm av forbindelsen fremstilt ifølge oppfinnelsen sammenblandet med et konvensjonelt drøvtygger-for; eller det kan ha form av en konsentrert premiks for for-tynning med et konvensjonelt drøvtyggerfor for å gi et supplementert for som er egnet for direkte foring, og en slik premiks vil inneholde fra 0,3 til 50% vekt/vekt av forbindelsen fremstilt ifølge oppfinnelsen sammenblandet med enten et konvensjonelt, ernæringsmessig avveiet drøvtyggerfor, et inert, fast fortynningsmiddel uten energiverdi, f.eks. malt kalksten, eller stivelse eller laktose. The preparation according to the invention can take the form of a feed with additives for direct feeding to animals, in which case it will contain from 5 to 3000 ppm of the compound produced according to the invention mixed with a conventional ruminant feed; or it may take the form of a concentrated premix for dilution with a conventional ruminant feed to provide a supplemented feed suitable for direct feeding, and such a premix will contain from 0.3 to 50% w/w of the compound prepared according to the invention mixed with either a conventional, nutritionally balanced ruminant feed, an inert, solid diluent without energy value, e.g. ground limestone, or starch or lactose.
I alle preparater ifølge oppfinnelsen som er beskrevet ovenfor, kan naturligvis forbindelsen ifølge oppfinnelsen er-stattes av en fermenteringsblanding eller en ekstrakt inneholdende en ekvivalent mengde av M139603. In all preparations according to the invention described above, the compound according to the invention can of course be replaced by a fermentation mixture or an extract containing an equivalent amount of M139603.
Et fast preparat kan fremstilles ved å blande jevnt én forbindelse, fermenteringsblanding eller -ekstrakt ifølge oppfinnelsen med en fast, spiselig, ikke-toksisk fortynner eller bærer. A solid preparation may be prepared by uniformly mixing one compound, fermentation mixture or extract of the invention with a solid, edible, non-toxic diluent or carrier.
Forbindelsen med formel I fortynnes fortrinnsvis i The compound of formula I is preferably diluted in
serie med fortynningsmidlet eller bæreren i to eller flere suksessive trinn for å sikre jevn sammenblanding. series with the diluent or carrier in two or more successive steps to ensure even mixing.
Oppfinnelsen skal illustreres, men ikke begrenses av følgende eksempler: Oppfinnelsen skal illustreres, men ikke begrenses av følgende eksempler: The invention shall be illustrated, but not limited, by the following examples: The invention shall be illustrated, but not limited, by the following examples:
Eksempel 1 Example 1
Streptomyces-arten NCIB 11426 ble dyrket i en 500 ml Erlenmeyer-kolbe på trypton-gjær-agar inneholdende: Trypton - "Oxoid" L42 (varemerke) 0,5% vekt/volum Gjærekstrakt - "Oxoid" L21 (varmerke) 0,3% vekt/volum som var forhåndssterilisert ved autoklavbehandling i 20 minutter ved normalt trykk. Mediets pH var ca. 7,0. Kolben ble rystet Streptomyces species NCIB 11426 was grown in a 500 ml Erlenmeyer flask on tryptone yeast agar containing: Tryptone - "Oxoid" L42 (trademark) 0.5% w/v Yeast extract - "Oxoid" L21 (trademark) 0.3 % weight/volume which had been pre-sterilized by autoclaving for 20 minutes at normal pressure. The pH of the medium was approx. 7.0. The flask was shaken
ved 25°C i 120 timer på en rotasjonsrystemaskin. at 25°C for 120 hours on a rotary shaker.
Innholdet i kolben ble så brukt til inokulering av ytterligere 10 lignende kolber som hver inneholdt 200 ml av følgende medium: The contents of the flask were then used to inoculate a further 10 similar flasks each containing 200 ml of the following medium:
Mediet ble forhåndssterilisert ved autoklavbehandling ved 120°C i 20 minutter efter at pH var justert til 7,2: De inokulerte kolbene ble rystet ved 25°C i 120 timer på en rotasjonsrystemaskin, og innholdet i kolbene ble så samlt og pH justert til 3 ved forsiktig tilsetning av 0,1N saltsyre. Mediet ble ekstrahert med etylacetat (2 x 600 ml), ekstraktene kombinert og tørket over natriumsulfat, og løsningsmidlet inndampet slik at det ble oppnådd en oljeaktig rest (290 mg). The medium was pre-sterilized by autoclaving at 120°C for 20 minutes after the pH was adjusted to 7.2: The inoculated flasks were shaken at 25°C for 120 hours on a rotary shaker, and the contents of the flasks were then collected and the pH adjusted to 3 by careful addition of 0.1N hydrochloric acid. The medium was extracted with ethyl acetate (2 x 600 mL), the extracts combined and dried over sodium sulfate, and the solvent evaporated to give an oily residue (290 mg).
Etylacetatekstrakten ble renset ved preparativ skiktkromatografi på to silikagel-plater (Mercks "kiselgel" 60F-254, 20 x 20 cm, 2 mm tykkelse) ved å bruke etylacetat som eluerings-middel. Båndet ved Rp = 0,39 (ca.) ble skrapet av platene og ekstrahert med etylacetat og løsningsmidlet ble inndampet slik at det ble oppnådd en viskøs gummi (21 mg), som in vitro viste antibakteriell aktivitet mot S. aureus. Denne aktive fraksjon ble ytterligere renset ved preparativ skiktkromatografi på en silikagelplate (Mercks "kiselgel" 60F-254, 20 x 20 cm, 0,25 mm tykkelse) ved å anvende en blanding av dietyletcr, metanol og maursyre i forholdet 95:4:1 (volumdeler). Båndet ved R r=0,55 (ca.) ble skrapet av platen og ekstrahert med etylacetat slik at det efter inndampning av løsningsmidlet ble oppnådd en viskøs gummi The ethyl acetate extract was purified by preparative layer chromatography on two silica gel plates (Merck "silica gel" 60F-254, 20 x 20 cm, 2 mm thickness) using ethyl acetate as eluent. The band at Rp = 0.39 (approx) was scraped off the plates and extracted with ethyl acetate and the solvent was evaporated to give a viscous gum (21 mg), which in vitro showed antibacterial activity against S. aureus. This active fraction was further purified by preparative layer chromatography on a silica gel plate (Merck "silica gel" 60F-254, 20 x 20 cm, 0.25 mm thickness) using a mixture of diethyl ether, methanol and formic acid in the ratio 95:4:1 (volume fractions). The band at R r=0.55 (approx.) was scraped off the plate and extracted with ethyl acetate so that after evaporation of the solvent a viscous gum was obtained
(9 mg). Gummien ble omdannet til et natriumsalt, M139603, (9mg). The gum was converted to a sodium salt, M139603,
ved å ryste en kloroformløsning med en løsning av natriumhydroksyd (0,1N). Kloroformskiktet ble fraseparert og tørket over natriumsulfat, og løsningsmidlet ble inndampet slik at M139603 ble oppnådd som et hvitt faststoff (8 mg), sm.p. 129-132°C, infrarødt spektrum (figur 1) oppviste følgende maksima: 3300, 1725, 1645, 1565 og 915 cm<-1.>by shaking a chloroform solution with a solution of sodium hydroxide (0.1N). The chloroform layer was separated and dried over sodium sulfate, and the solvent was evaporated to give M139603 as a white solid (8 mg), m.p. 129-132°C, infrared spectrum (figure 1) showed the following maxima: 3300, 1725, 1645, 1565 and 915 cm<-1.>
Elementæranalyse: Elemental analysis:
Beregnet for C^H^OgNa: C 67,3, H 8,5% Calculated for C^H^OgNa: C 67.3, H 8.5%
Funnet: C 6 7,5, H 8,8. Found: C 6 7.5, H 8.8.
Massespektrum: M = 624,361, beregnet for C35<H>53<0gN>a = 624,364. Mass spectrum: M = 624.361, calculated for C35<H>53<0gN>a = 624.364.
Rp = 0,39 (tynnskiktkromatografi) på Mercks 60F-254, 0,25 mm Rp = 0.39 (thin layer chromatography) on Merck's 60F-254, 0.25 mm
plater utviklet med etylacetat, synliggjort som en brun flekk efter påsprøyting med 3N svovelsyre og oppvarmhing til 100°C. plates developed with ethyl acetate, visible as a brown spot after spraying with 3N sulfuric acid and heating to 100°C.
Det protonmagnetiske resonansspektrum i deuteriokloroform The proton magnetic resonance spectrum in deuteriochloroform
er gjengitt i figur 2. is reproduced in Figure 2.
E ksempel 2 Example 2
Evnen hos M139603 til å hindre produksjonen av metan The ability of M139603 to prevent the production of methane
i rumen hos drøvtyggere, og øke mengden propionat på bekostning av acetat (Ac/Pr) i de produserte flyktige fettsyrer, påvises som følger: Rumen-væske oppsamles på en regulær rutinebasis fra to okser, som fores på samme høy-pluss-konsentrat-diett. Prøve-tagningstiden standardiseres så godt som mulig, og væsken fra de to dyrene samles på 50/50-basis. Store, partikkelformige stoffer fjernes ved filtrering av den samlede væske gjennom fire skikt av musselin-tøy. Filtratet fortynnes så i forholdet ett volum filtrat til tre volumer av en kunstig rumenvæske (fremstilt som beskrevet av G.L. Bales et al., Journal of Diary Science, 1976, vol. 59, side 1850, men med utelatelse av eddiksyre), og pH i blandingen justeres til 6,9-7,0 med mettet, vandig natriumkarbonat-løsning. Alikvotcr (50 ml) av denne blanding fordeles til 100 ml koniske kolber inneholdende tørket, malt høy (0,5 g), og hver kolbe brukes for å teste en testforbindelse in the rumen of ruminants, and increase the amount of propionate at the expense of acetate (Ac/Pr) in the produced volatile fatty acids, is demonstrated as follows: Rumen fluid is collected on a regular routine basis from two bulls, which are fed on the same hay plus concentrate diet. The sampling time is standardized as much as possible, and the fluid from the two animals is pooled on a 50/50 basis. Large, particulate substances are removed by filtering the combined liquid through four layers of muslin cloth. The filtrate is then diluted in the ratio of one volume of filtrate to three volumes of an artificial rumen fluid (prepared as described by G.L. Bales et al., Journal of Diary Science, 1976, vol. 59, page 1850, but omitting acetic acid), and the pH in the mixture is adjusted to 6.9-7.0 with saturated aqueous sodium carbonate solution. Aliquots (50 ml) of this mixture are dispensed into 100 ml conical flasks containing dried, ground hay (0.5 g) and each flask is used to test a test compound
ved en spesiell konsentrasjon. at a particular concentration.
Testforbindelsen tilsettes til den koniske kolben som The test compound is added to the conical flask which
en løsning i etanol, kolben gjennomblåses med karbondioksydgass, tettes med en "suba"-forsegling og inkuberes ved 39°C i 15-16 timer. Efter én times forløp innføres en nål gjennom "suba"-forseglingen for å avlaste gasstrykket, og nålen trekkes ut 30 minutter før inkuberingen avsluttes. Fermenteringen stanses så ved å plassere kolben i is, og efter 15 minutters avkjøling analyseres gassen over væsken på metan ved gasskromatografi. Kolbeinnholdet filtreres så gjennom en på forhånd tørket, sintret glasstrakt. a solution in ethanol, the flask is purged with carbon dioxide gas, sealed with a "suba" seal and incubated at 39°C for 15-16 hours. After one hour, a needle is inserted through the "suba" seal to relieve the gas pressure, and the needle is withdrawn 30 minutes before the incubation ends. Fermentation is then stopped by placing the flask in ice, and after 15 minutes of cooling, the gas above the liquid is analyzed for methane by gas chromatography. The contents of the flask are then filtered through a pre-dried sintered glass funnel.
Tre prøver av filtratet analyseres ved gasskromatografi på VFA, Three samples of the filtrate are analyzed by gas chromatography on VFA,
og ved sammenligning med det på forhånd bestemte før-inkuberings-nivå av VFA bestemmes netto VFA (acetat og propionat) produsert under inkuberingen. and by comparison with the predetermined pre-incubation level of VFA, the net VFA (acetate and propionate) produced during the incubation is determined.
Følgende resultater ble oppnådd, uttrykt som % av kontrollverdier oppnådd når det ikke anvendes noen testforbindelse. Monensin, en kjent vekstfremmer som virker ved å The following results were obtained, expressed as % of control values obtained when no test compound is used. Monensin, a well-known growth promoter that works by
påvirke rumen, anvendes som positiv kontroll. affect the rumen, is used as a positive control.
Eksempel 3 Example 3
Streptomyces longisporoflavus NCIB 11426 ble dyrket som skråkulturer på ISP7-agar (45 ml) i 7 dager ved 30°C. Tre slike skrå-agarkulturer ble enkeltvis skrapet over i tre kolber med 100 ml sterilt vann, og de således oppnådde suspensjoner ble brukt til inokulering av tre 2 liters kolber som hver inneholdt 1 liter av følgende medium: Streptomyces longisporoflavus NCIB 11426 was grown as slant cultures on ISP7 agar (45 ml) for 7 days at 30°C. Three such slanted agar cultures were individually scraped into three flasks with 100 ml of sterile water, and the thus obtained suspensions were used to inoculate three 2 liter flasks, each containing 1 liter of the following medium:
som på forhånd var sterilisert ved autoklavbehandling ved normalt trykk i 1/2 time, idet pH var ca. 6,7. which had previously been sterilized by autoclaving at normal pressure for 1/2 hour, the pH being approx. 6.7.
De tre på denne måten preparerte kolber ble så rystet ved 30°C i 5 dager i en rotasjonsrystemaskin. Innholdet i de tre kolbene ble så kombinert og brukt til inokulering av en fermenteringsbeholder av rustfritt stål inneholdende 30 1 sterilisert medium fremstilt av følgende: The three flasks prepared in this way were then shaken at 30°C for 5 days in a rotary shaker. The contents of the three flasks were then combined and used to inoculate a stainless steel fermentation vessel containing 30 L of sterilized medium prepared from the following:
Innholdet i fermenteringsbeholderen ble omrørt ved 30°C i 70 timer ved å bruke en turbin med 4 flate blad som roterte med cn hastighet av 350 rpm, og luftet med en mengde på 15 liter pr. minutt. Før autoklavbehandlingen var det til blandingen tilsatt 30 ml "Silicolapse", et silikon-antiskum-middel. Ved høstingen var pH 7,9, og den resulterende fermenteringsblanding (22 liter) ble blandet og omrørt med et like stort volum etylacetat. Efter 30 minutters forløp ble blandingen separert i en sentrifuge-separator, og etylacetatekstrakten (ca. 18 1) ble tørket over vannfritt natriumsulfat og filtrert. Filtratet ble konsentrert under redusert trykk slik at det ble oppnådd en oljeaktig rest (10,7 g). The contents of the fermenter were stirred at 30°C for 70 hours using a turbine with 4 flat blades rotating at a speed of 350 rpm, and aerated at a rate of 15 liters per minute. minute. Before the autoclave treatment, 30 ml of "Silicolapse", a silicone antifoam agent, was added to the mixture. At harvest, the pH was 7.9, and the resulting fermentation mixture (22 liters) was mixed and stirred with an equal volume of ethyl acetate. After 30 minutes, the mixture was separated in a centrifuge separator, and the ethyl acetate extract (about 18 L) was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oily residue (10.7 g).
M139603 ble oppnådd fra ovenstående konsentrat ved hjelp av følgende fremgangsmåte: M139603 was obtained from the above concentrate by the following procedure:
Den oljeaktige resten (10,7 g) ble oppløst i et minimalt volum etylacetat, og den resulterende løsning ble påført på toppen av en kolonne med nøytralt aluminiumoksyd (Woelm N, 200 g, 18 cm x 4 cm) fremstilt som en oppslemming i etylacetat. Kolonnen ble først eluert med etylacetat, fulgt av en 50% vekt/vekt blanding av etylacetat og metanol, og til slutt med metanol. Følgende fraksjoner ble oppsamlet etter at løsningsmiddeltronten var kommet frem fra kolonnen: The oily residue (10.7 g) was dissolved in a minimal volume of ethyl acetate and the resulting solution was applied to the top of a column of neutral alumina (Woelm N, 200 g, 18 cm x 4 cm) prepared as a slurry in ethyl acetate . The column was first eluted with ethyl acetate, followed by a 50% w/w mixture of ethyl acetate and methanol, and finally with methanol. The following fractions were collected after the solvent column had emerged from the column:
Fraksjonene 7-11, inklusive, ble ved hjelp av tynnskiktkromatografi på silikagel utviklet med 20% vekt/vekt aceton i petroleter (k.p. 60-80°C), påvist å inneholde M139603 Fractions 7-11, inclusive, were shown to contain M139603 by means of thin-layer chromatography on silica gel developed with 20% w/w acetone in petroleum ether (b.p. 60-80°C)
(R„ r ^ 0,22) og de ble kombinert og inndampet slik at det ble (R„ r ^ 0.22) and they were combined and evaporated to leave
oppnådd en viskøs gummi (840 mg) som ble renset ytterligere ved preparativ skiktkromatografi på silikagel (Mercks "kiselgel 60F-250", 40 cm x 20 cm, 2 mm tykkelse) ved å bruke en blanding av 20% vekt/vekt aceton i petroleter (k.p. 60-80°C) som eluerings-middel. Det UV-synlige båndet ved Rp MD,22 (ca.) ble skrapet fra de to platene og ekstrahert med etylacetat, og ekstrakten ble inndampet til tørrhet for å gi en viskøs gummi (240 mg), som krystalliserte ved tilsetning av petroleter (k.p. 60-80°C). obtained a viscous gum (840 mg) which was further purified by preparative layer chromatography on silica gel (Mercks "silica gel 60F-250", 40 cm x 20 cm, 2 mm thickness) using a mixture of 20% w/w acetone in petroleum ether (b.p. 60-80°C) as eluent. The UV-visible band at Rp MD,22 (approx) was scraped from the two plates and extracted with ethyl acetate, and the extract was evaporated to dryness to give a viscous gum (240 mg), which crystallized on addition of petroleum ether (b.p. 60-80°C).
Dette materiale ble omkrystallisert fra petroleter (k.p. 60-80°C) for å gi M139603 som farveløse krystaller som ble avfiltrert og tørket (210 mg), sm.p. 176-178°C. Ultrafiolett spektrum i etanol viste absorpsjoner ved 234 nm (r = 12900) og 272 nm ( z = 10800). Infrarødt og kjernemagnetisk resonans-spektrum var identiske med de som ble oppnådd fra produktet i eksempel 1. This material was recrystallized from petroleum ether (b.p. 60-80°C) to give M139603 as colorless crystals which were filtered off and dried (210 mg), m.p. 176-178°C. Ultraviolet spectrum in ethanol showed absorptions at 234 nm (r = 12900) and 272 nm (z = 10800). Infrared and nuclear magnetic resonance spectra were identical to those obtained from the product of Example 1.
Eksempel 4 Example 4
M139603 (40 mg) ble oppløst i en blanding av aceton M139603 (40 mg) was dissolved in a mixture of acetone
(10 ml) og vann (2 ml), 1 ml 2N saltsyre ble tilsatt og blandingen ble omrørt kraftig i 5 minutter. Destillert vann (20 ml) ble tilsatt og blandingen ble ekstrahert med diklormetan (2 x 10 ml). Det organiske skiktet ble fraskilt og vasket med 2N saltsyre, fulgt av destillert vann. Diklormetanskiktet ble så konsentrert for å gi en viskøs gummi (33 mg) av den "frie syren" som er ekvivalent med M139603. (10 ml) and water (2 ml), 1 ml of 2N hydrochloric acid was added and the mixture was stirred vigorously for 5 minutes. Distilled water (20 mL) was added and the mixture was extracted with dichloromethane (2 x 10 mL). The organic layer was separated and washed with 2N hydrochloric acid, followed by distilled water. The dichloromethane layer was then concentrated to give a viscous gum (33 mg) of the "free acid" equivalent to M139603.
Elementæranalyse: Elemental analysis:
Beregnet for C35H54<0:> C 69,8, H 9,0 Calculated for C35H54<0:> C 69.8, H 9.0
Funnet: C 69,5, H 8,1 Found: C 69.5, H 8.1
IR-spektrum i nujol "mull", som vist i figur 3, inneholdende karakteristiske absorpsjoner ved 3500, 1765, 1685, 1650, IR spectrum in nujol "mull", as shown in Figure 3, containing characteristic absorptions at 3500, 1765, 1685, 1650,
1575 cm ^ ; det protonmagnetiske resonans-spektrum i deuteriokloroform er vist i figur 4. 1575 cm ^ ; the proton magnetic resonance spectrum in deuteriochloroform is shown in Figure 4.
Eksempel 5 Example 5
Den "frie syren" som er ekvivalent med M139603 (30 mg) ble oppløst i en blanding av tetrahydrofuran (7 ml) og vann (1 ml). Et alkalimetallhydroksyd, X0H (2N, 2 ml) ble tilsatt til den vandige tetrahydrofuranblandingen som så ble omrørt kraftig i 10 minutter. Vann (10 ml) ble tilsatt og oppløsningen ble ekstrahert med eter (2 x 15 ml). Eterekstraktene kombineres og inndampes for å gi de alkalimetallsalter som tilsvarer natriumsaltet, M139603. The "free acid" equivalent to M139603 (30 mg) was dissolved in a mixture of tetrahydrofuran (7 mL) and water (1 mL). An alkali metal hydroxide, XOH (2N, 2 mL) was added to the aqueous tetrahydrofuran mixture which was then stirred vigorously for 10 minutes. Water (10 mL) was added and the solution was extracted with ether (2 x 15 mL). The ether extracts are combined and evaporated to give the alkali metal salts corresponding to the sodium salt, M139603.
Når X = kalium dannes kaliumsaltet, sm.p. 146-150°C, molekylformel C35fI53°gK som indikert ved massespektrometri , When X = potassium, the potassium salt is formed, m.p. 146-150°C, molecular formula C35fI53°gK as indicated by mass spectrometry,
som viser et molekylært ion, M<+>, med masse 640.335 (beregnet for <C>35H53°gK= 640,339), og ved elementæranalyse: which shows a molecular ion, M<+>, with mass 640.335 (calculated for <C>35H53°gK= 640.339), and by elemental analysis:
Beregnet for C^H^OgK: C = 65,6%, H 8,3%, Calculated for C^H^OgK: C = 65.6%, H 8.3%,
funnet: C = 65,7%, H 8,3%). found: C = 65.7%, H 8.3%).
Når X er rubidium dannes rubidiumsaltet, sm.p. 95-120°C, molekylformel C-^Hc-30gRb, som indikert ved massespektrometri, When X is rubidium, the rubidium salt is formed, m.p. 95-120°C, molecular formula C-^Hc-30gRb, as indicated by mass spectrometry,
som viser et molekylært ion, M<+>, med masse 686,279 (beregnet for C35H530gRb=686,286). which shows a molecular ion, M<+>, with mass 686.279 (calculated for C35H530gRb=686.286).
Eksempel 6 Example 6
Evnen for M139603 til a øke mengden propionat på bekostning av acetat i rumenvæsken hos sauer ble påvist som følger: 23 sauer ble holdt i hvert sitt rom og foret med samme diett på 1 kg av tørkede gressterninger pr,, dyr pr. dag. Dyrene ble fordelt tilfeldig med 13 som negative kontroller, 5 som positive kontroller ved bruk av monensin, en kjent rumen-manipulator, og 5 som ble tilført M139603. De behandlede dyrene ble gitt monensin eller M139603 oralt i en mengde av 0,5 mg/kg på hver av de fire suksessive dager, og prøver av rumenvæske ble oppsamlet ved maverør 6 timer efter behandling på dag 4. Rumenvæskeprøvene ble så analysert på acetat og propionat som beskrevet i eksempel 2. De resultater som ble oppnådd, var som følger: The ability of M139603 to increase the amount of propionate at the expense of acetate in the rumen fluid in sheep was demonstrated as follows: 23 sheep were kept in separate rooms and fed the same diet of 1 kg of dried grass cubes per animal per animal. day. Animals were randomly assigned with 13 as negative controls, 5 as positive controls using monensin, a known rumen manipulator, and 5 given M139603. The treated animals were given monensin or M139603 orally in an amount of 0.5 mg/kg on each of the four successive days, and samples of rumen fluid were collected by gastric tube 6 hours after treatment on day 4. The rumen fluid samples were then analyzed for acetate and propionate as described in Example 2. The results obtained were as follows:
Acetatresponsen for M138603 er signifikant ved p<0,02, sammenlignet med den positive kontrollen, monensin; og propionat-responsen for M139603 er signifikant ved p<0,001 sammenlignet med den positive kontrollen, monensin. The acetate response for M138603 is significant at p<0.02, compared to the positive control, monensin; and the propionate response for M139603 is significant at p<0.001 compared to the positive control, monensin.
Claims (2)
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NO792537A NO156201C (en) | 1978-08-03 | 1979-08-02 | A STREPTOMYCES METABOLITE M139603 WHICH, BY ADDING TO LINES, IMPROVES THE GROWTH SPEED OF DRUGS. |
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US (1) | US4279894A (en) |
JP (1) | JPS5551097A (en) |
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FI (1) | FI66184C (en) |
FR (1) | FR2433578A1 (en) |
HK (1) | HK26185A (en) |
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SG (1) | SG54784G (en) |
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EP0070622B1 (en) * | 1981-07-16 | 1987-01-14 | Imperial Chemical Industries Plc | Derivatives of m.139,603 useful as growth promotors |
JPS60141293A (en) * | 1983-12-28 | 1985-07-26 | Kitasato Inst:The | Novel carcinostatic antibiotic substance 81-484 and its production |
AU581691B2 (en) * | 1985-10-14 | 1989-03-02 | Balfour Manufacturing Company Limited | Process for the production of feedstuffs |
US4675270A (en) * | 1986-02-10 | 1987-06-23 | Loctite (Ireland) Limited | Imaging method for vapor deposited photoresists of anionically polymerizable monomer |
US5023086A (en) * | 1987-03-13 | 1991-06-11 | Micro-Pak, Inc. | Encapsulated ionophore growth factors |
US4876273A (en) * | 1987-08-13 | 1989-10-24 | Eli Lilly And Company | Antibotic A80577 and process for its production |
US5985907A (en) * | 1998-08-12 | 1999-11-16 | Health Research, Inc. | Method for inhibiting growth of methanogens |
CN113150995A (en) * | 2021-04-22 | 2021-07-23 | 贵州安康医学检验中心有限公司 | Bacterium transferring and preserving culture medium used in transferring process and preparation method thereof |
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1979
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